Sevelamer, or poly(allylamine-co-N,N′-diallyl-1,3-diamino-2-hydroxypropane), is a polymer compound having the formula
wherein a+b=9; c=1; and m is variable,
Sevelamer is marketed as the hydrochloride salt under the trade name Renagel® for controlling hyperphosphatemia (increase in the level of phosphates in the blood) in adult patients undergoing dialysis or hemodialysis. Recently, the sevelamer carbonate/bicarbonate salt, under the trade name Renvela®, has also been placed on the market.
Different types of the synthesis of sevelamer are known, all substantially deriving from cross-linking with high molecular weight polyallylamine epichlorohydrin.
Polyallylamine is a polymer compound known in the art with the CAS RN 71550-12-4 and is obtained by allylamine polymerization.
One of the major problems encountered during the synthesis of sevelamer is the production of a highly congealed and viscous reaction mass, which must be adequately stirred and crumbled in order to obtain a final product in solid form.
Some patent documents describe the synthesis of sevelamer by reaction between an aqueous solution of polyallylamine and epichlorohydrin in an organic solvent, such as toluene or acetonitrile. The use of the organic solvent is necessary in order to process the congealed and difficult to process mass, as seen above.
U.S. Pat. No. 6,180,754 in the name of The Dow Chemical Company, describes a process for the synthesis of sevelamer that provides for the use of a LIST reactor to perform the cross-linking step. This reactor, produced by the company LIST Inc., is a reactor specifically designed for processing high viscosity materials. It is easily understood that this reactor is not commonly used and that its use requires specific and economically important investments, unjustified for the preparation of a single active ingredient.
The patent application WO01/18072 describes a process for the preparation of sevelamer hydrochloride comprising partial desalification of a solution of polyallylamine hydrochloride, removal of salts through ion exchange or electrodeionization and by means of subsequent optional nanofiltration or ultrafiltration of the partially desalified polyallylamine, and then causing it to react with epichlorohydrin. As stated in the text of WO01/18072 (for example pages 4 and 5), during desalification of the polyallylamine hydrochloride with metal hydroxides a substantial quantity of salts is produced. The steps of removing salts and of nanofiltration or ultrafiltration are therefore necessary, as otherwise a very viscous and non-stirrable mixture is obtained during the subsequent cross-linking reaction with epichlorohydrin. This mass would require the use of a LIST reactor as seen above or, alternatively, the addition of substantial quantities of organic solvents.
It is evident that these further reaction steps are laborious and entail substantial costs at industrial level.